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Keywords:

  • Crossmatching;
  • highly sensitized;
  • histocompatibility;
  • HLA antibodies;
  • kidney allocation

Abstract

  1. Top of page
  2. Abstract
  3. Data and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure:
  8. References

The calculated panel reactive antibody (CPRA), which is based upon unacceptable HLA antigens listed on the waitlist form for renal transplant candidates, replaced PRA as the measure of sensitization among US renal transplant candidates on October 1, 2009. An analysis of the impact of this change 6 months after its implementation shows an 83% reduction in the number of kidney offers declined nationwide because of a positive crossmatch. The increasing acceptance and utilization of unacceptable HLA antigens to avoid offers of predictably crossmatch-positive donor kidneys has increased the efficiency of kidney allocation, resulting in a significant increase in the percentage of transplants to broadly sensitized (80+% PRA/CPRA) patients from 7.3% during the period 07/01/2001–6/30/2002 to 15.8% of transplants between 10/1/09–3/31/10. The transplant rates per 1000 active patient-years on the waitlist also increased significantly for broadly sensitized patients after October 1, 2009. These preliminary results suggest that ‘virtual’ positive crossmatch prediction based on contemporary tools for identifying antibodies directed against HLA antigens is effective, increases allocation efficiency and improves access to transplants for sensitized patients awaiting kidney transplantation.

Abbreviations: 
CPRA

calculated panel reactive antibody

OPTN

Organ Procurement and Transplantation Network

PRA

panel reactive antibody

UNOS

United Network for Organ Sharing

The Organ Procurement and Transplantation Network (OPTN) administered by the United Network for Organ Sharing (UNOS) established the calculated panel-reactive antibody (CPRA) in December 2007 to provide a more uniform and accountable method for assessing sensitization to HLA antigens. The CPRA is based upon unacceptable HLA antigens, which are determined by each transplant program based on the risk they attribute to circulating antibodies in a candidate's serum directed against those specific HLA antigens (1). The unacceptable antigens represent a positive ‘virtual’ crossmatch. The OPTN does not offer organs from donors who express unacceptable HLA antigens to patients for whom these antigens are listed, so organ offers from donors who are predictably incompatible with the candidate are avoided.

The establishment of CPRA was made possible by the growing utilization of solid-phase tests to detect anti-HLA antibodies using both single HLA phenotypes and single HLA antigens. These tests allowed laboratories to identify individual HLA antigen targets with precision, even for patients who were broadly sensitized. Although the OPTN has always given centers the option to list unacceptable HLA antigens (2), precise identification of the HLA antigen targets of the antibody response in broadly sensitized patients was often difficult prior to the solid-phase tests. The use of unacceptable HLA antigens to prevent offers from predictably crossmatch-incompatible donors increased during the period 2003–2009 (3–7).

CPRA represents a fundamental change in the measurement of sensitization. Prior to the implementation of CPRA, transplant centers and laboratories could report a PRA value based on any of a variety tests with widely differing sensitivities and specificities. The CPRA policy requires laboratories to enter the specific unacceptable HLA antigens identified for their candidates in the OPTN computer system. The computer automatically calculates CPRA based on HLA frequencies derived from the US donor population. The CPRA represents the percentage of potential donors that will be preemptively declined due to the presence of one or more unacceptable antigens. The requirement to list unacceptable antigens instead of a PRA value was the real change that tied accountability to sensitization. In order to receive four extra allocation points for a renal candidate, the center must preemptively decline at least 80% of potential donors that might be offered to that patient. The expectations for CPRA were that it would provide consistency and accountability to reporting sensitization, and that it would improve kidney allocation efficiency by reducing incompatible offers, reducing positive crossmatches for patients at the top of the waiting list and increasing the chances for broadly sensitized patients to be transplanted with a compatible organ (1).

On October 1, 2009, the OPTN replaced the measured panel-reactive antibody (PRA) fields that had previously defined sensitization with CPRA and CPRA replaced PRA in kidney allocation (OPTN Policy 3.5.11.3). The OPTN/UNOS Histocompatibility Committee has monitored the implementation of CPRA since it first appeared on December 5, 2007. Between December 5, 2007 and October 1, 2009, centers reported their own PRA value (based upon a test result or based on CPRA), for their patients, but were required to use at least one solid-phase antibody test and to enter at least one unacceptable antigen for the patient to be eligible for four additional allocation points for patients with a PRA of 80+%.

Here we report the early results at the national level following the replacement of PRA with CPRA as they relate to the changes in patterns of reported sensitization, the effects of sensitization under the new definition on the rate of positive crossmatches, and transplantation of sensitized patients before, during and after implementation of CPRA.

Data and Methods

  1. Top of page
  2. Abstract
  3. Data and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure:
  8. References

All results are based on OPTN data as of June 11, 2010. CPRA was automatically calculated for kidney, kidney pancreas and pancreas candidates after December 5, 2007. Between December 5, 2007 and October 1, 2009, the CPRA appeared on the waitlist form together with the measured PRA values that were reported, but was not utilized for kidney allocation. Prior to October 1, 2009 kidney allocation was based on the PRA value designated by the transplant center for allocation and since that date allocation has been based on CPRA.

Allocation PRA is defined as the current PRA if the waiting list record indicated that the current PRA was to be used for allocation and peak PRA if the peak PRA was indicated. CPRA is defined as the percentage of donors expected to have one or more of the unacceptable HLA antigens indicated on the waiting list for the candidate. CPRA defaults to zero if no unacceptable antigens are entered. Some unacceptable HLA antigens are sufficiently rare that the CPRA value rounds to zero; however, kidneys from donors with those rare antigens are not offered to the patient. The CPRA is based on HLA-A,-B,-DR and -DQ frequencies derived from the phenotypes of 12 061 donors in the OPTN registry as previously described (8). The HLA-C antigens are currently excluded from the CPRA calculation because there was inadequate donor typing data to estimate their frequencies. Entry of unacceptable HLA-C locus antigens will prevent offers for donors typed for those antigens.

We compared the CPRA distribution for kidney registrations listed on 3/31/10 (6 months after CPRA replaced PRA as the measure of sensitization) with allocation PRA distributions for kidney registrations listed on 6/30/01, 6/30/02 (before the widespread availability of single HLA antigen tests that greatly increased the accuracy of HLA antibody identification) and 3/31/09 (6 months before the change to CPRA).

We analyzed the numbers of positive crossmatches reported as a reason for declining an organ offer for deceased donor kidney match runs performed during 07/01/2001–12/31/2001, 01/01/2002–06/30/2002, 04/01/2009–09/30/2009 and 10/01/2009–03/31/2010 stratified by candidate sensitization levels (0, 1–20, 21–79, 80+% PRA/CPRA). These periods were chosen to represent the use of preliminary crossmatch trays to prevent positive crossmatches for sensitized candidates (2001–2002), a mixture of preliminary crossmatches and unacceptable antigens (ending on 9/30/2009) and current practice (after 10/1/2009).

The number of kidney organ offers that were declined due to positive crossmatches included those reported as due to a positive crossmatch result for deceased donors with at least one kidney transplanted. When other reasons for declining an offer were reported but text fields clearly indicated that the offer was declined because of a positive crossmatch, these were counted as well.

The analyses include those candidates listed at more than one center since they would have multiple registrations. For comparison with CPRA (which defaults to 0% whether a patient is unsensitized or has not been tested), PRA values of 0% and those not reported were combined into one group in Figure 1 and Tables 2 and 3.

image

Figure 1. Allocation PRA/CPRA patterns for registrants on the active waiting list at four time points.

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Table 2.  Deceased donor kidney transplants by era and recipient's sensitization level
Allocation PRA/CPRA group (%)Era
07/01/2001–12/31/200101/01/2002–06/30/200204/01/2009–09/30/200910/01/2009–03/31/2010
N%N%N%N%
  1. *Patients with zero CPRA cannot be distinguished from those with no report, so these groups were combined for each time interval.

0/Not reported*273264.7272464.9290554.9321765
1–20 83719.8 82019.5 90217 278 5.6
21–79 349 8.3 346 8.2 74314 67313.6
80+ 303 7.2 307 7.3 74514.1 78515.8
All4221100419710052951004953100
Table 3.  Transplant rates per 1000 active patient-years for adult kidney alone registrations on the waiting list (WL) by sensitization level
Allocation PRA/CPRA07/01/2001–12/31/200101/01/2002–06/30/200204/01/2009–09/30/200910/01/2009–03/31/2010
No. of transplantsTx rate per 1000 Pt-YrsNo. of transplantsTx rate per 1000 Pt-YrsNo. of transplantsTx rate per 1000 Pt-YrsNo. of transplantsTx rate per 1000 Pt-Yrs
  1. *Patients with zero CPRA cannot be distinguished from those with no report, so these groups were combined for each time interval.

0/Not reported*2558192.32703202.62602177.32945 165.0
1–20 763221.0 609181.2 817221.8224178.7
21–79 335145.5 285119.0 667189.5595190.4
80+ 249129.7 203103.3 591158.2647166.1
80–84  49194.1  29118.9 138358.5157489.3
85–89  36144.0  33128.3  96223.5144376.9
90–95  67139.9  64128.5 145171.3167238.9
>95  97 97.8  77 75.5 212 97.1179 69.3

Transplant rates for adult kidney alone registrations ever on the waiting list during the four 6-month periods were calculated based on active waiting time per 1000 patient-years. These rates are based on the allocation PRA/CPRA value at the beginning of the time period or at listing, whichever came first.

The chi-square statistic was used to compare percentages between groups and the delta method was used to compare differences in transplant rates.

Results

  1. Top of page
  2. Abstract
  3. Data and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure:
  8. References

CPRA was rapidly utilized by laboratories after it was available on the UNetSM waitlist. On 3/31/08, 4 months after CPRA was available, only 13 (5%) of 256 centers had not listed any unacceptable antigens for any kidney patients. On 3/31/2010, 6 months after CPRA replaced PRA on the waitlist form, only 10 (4%) of the 255 US transplant programs had not listed any unacceptable antigens for at least one candidate on their waitlist. Only 3 of the 10 programs had more than 10 candidates listed. The median numbers of unacceptable antigens listed for candidates with 1–20%, 21–79% and 80+% CPRA were 2, 5 and 35, respectively.

Figure 1 shows the distribution of allocation PRA/CPRA values for kidney registrants on 6/30/2001, 6/30/2002, 3/31/2009 and 3/31/2010 (distributions during the 2001 and 2002 intervals are nearly identical). The percentage of unsensitized or unreported registrants declined slightly from 61% of registrants in 2001 and 2002 to 56% in 2009. However, 6 months after CPRA replaced PRA, 66% of registrants were reported as unsensitized. The numbers of broadly sensitized registrants (80+%) had already increased prior to implementation of CPRA (3/31/2009) and remained at similar levels following its replacement of PRA. Nearly all of that increase was among registrants with >95% PRA/CPRA. The percentages of registrants who had >95% PRA/CPRA were 5.3%, 5.4%, 8.6% and 10.2% at the four time points, respectively (p < 0.001 comparing the 2001–2002 periods with each of the most recent 6-month periods).

Following the introduction of CPRA, there was a substantial reduction in the number of positive crossmatches reported as reasons for declining a kidney offer as shown in Table 1. During the 6-month periods in 2001 and 2002, there were 28 144 and 27 717 positive crossmatches reported, compared with 15 579 during the 6 months prior to CPRA and 2724 following the change to CPRA. During the 6 months prior to the formal change to CPRA, the incidence of positive crossmatches had already been reduced by more than 40% as a result of unacceptable antigens that were entered. There was a further 83% decrease after the change to CPRA. Overall the decrease was about 90%, comparing the rates after CPRA implementation to those during the 2001 and 2002 periods, when patients were primarily screened by a preliminary crossmatch. This precipitous drop in the number of offers that were declined due to a positive crossmatch was apparent among each of the sensitization groups, but was most striking for broadly sensitized patients (80+% PRA/CPRA) where it fell by 87% following the change to CPRA (p < 0.001). During the 6 months prior to CPRA, positive crossmatches increased by about 50% in the 0% PRA/CPRA group compared with the earlier periods, but decreased by 75% following the change to CPRA. During the same periods, the number of transplants increased by 17.3% from 4221 during 07/01/2001–12/31/2001 to 4953 during 10/01/2009–3/31/2010, indicating that the number of kidneys offered was relatively comparable during each interval.

Table 1.  Number of positive crossmatches reported as a reason for organ refusal
Allocation PRA/CPRA group (%)Era
07/01/2001–12/31/200101/01/2002–06/30/200204/01/2009–09/30/200910/01/2009–03/31/2010
Not reported5896775880
03270315550061288
1–20205118001715134
21–79573550402477565
80+16 49917 0455793737
All28 14427 71715 5792724
Deceased donor kidney transplants4221419752954953

If laboratories and transplant programs had set their thresholds very low for defining unacceptable antigens, we might expect a sharp reduction in positive crossmatches as the more broadly sensitized patients would not be offered kidneys. However, the number and percentage of transplants among sensitized patients actually increased during and following implementation of CPRA (Table 2). During 2001 and 2002, 7.2–7.3% of transplants went to patients with 80+% PRA. The percentage of transplants to these broadly sensitized patients doubled to 14.1% and 15.8% during and after implementation of CPRA. The trend was similar for patients with 21–79% PRA/CPRA during the four time periods.

We also analyzed transplants rates per 1000 active patient-years on the waitlist for adult kidney alone waitlist registrants to account for changes to the waitlist over time (Table 3). Transplant rates increased significantly for patients with 21–79 and 80+% CPRA during the transition to CPRA and after CPRA replaced PRA (p < 0.05) comparing the first two periods with each of the later periods). A breakdown of the broadly sensitized patients showed that transplant rates increased after CPRA implementation for each group with the exception of those patients with >95% CPRA. During two of the three earlier periods, patients with >95% PRA were transplanted at a higher rate.

Discussion

  1. Top of page
  2. Abstract
  3. Data and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure:
  8. References

The goals of introducing the CPRA were to provide a more consistent and accountable measure of sensitization among kidney transplant candidates. The unacceptable antigens that are listed to generate the CPRA represent a positive ‘virtual’ crossmatch by defining those HLA antigens that would be unacceptable in a donor. Among the anticipated effects of implementing CPRA was an increase in the efficiency of organ allocation by reducing the number of positive crossmatches that would prevent the candidate at the top of the local waiting list from being allocated the donor organ.

Importantly, several groups had already reported increased transplantation of sensitized patients using the virtual crossmatch (3,4,9). This study of the early experience with CPRA appears to support these expectations. The number of kidney offers declined due to a positive crossmatch fell substantially during and following the change to CPRA. This occurred despite a 17.3% rise in the number of transplants that were performed.

The change to CPRA as a measure of sensitization was only possible with the introduction of solid-phase technologies that permitted precise identification of HLA antigens to which a patient had circulating antibodies that began to be widely used in 2003. These changes in practice evolved during the interval from 2003–2009 and continue to evolve. The move to a national policy that would measure sensitization based only upon unacceptable HLA antigens began in response to the widely variable PRA values that were being reported as a result of the introduction of the solid-phase test platforms (1). Thus, the implementation of CPRA as a policy gave impetus to changes that were already occurring at many centers and laboratories in the United States to adapt a uniform measure of sensitization. Declining kidneys preemptively based upon the HLA type of the donor eliminated most offers that were turned down due to a positive crossmatch. The nearly 10-fold decrease in the number of positive crossmatches using virtual rather than actual crossmatches, if sustained, should result in more efficient kidney allocation, shorter cold ischemia times, fewer offers of incompatible kidneys and time savings for OPO and laboratory personnel. Although this change occurred over a period of 7 years in the United States, each individual center that made this change during that time likely observed a similar decline in positive crossmatches when they began listing unacceptable antigens for their sensitized patients.

It appears that sensitized patients benefited from the migration to CPRA as well, since the percentages of sensitized patients who were transplanted increased and more than doubled from 7% to nearly 16% among those with 80+% CPRA. The increase in transplantation of broadly sensitized patients suggests that listing unacceptable antigens to represent the degree of sensitization has enhanced the likelihood that sensitized candidates who are offered a kidney will have a negative crossmatch. Those patients then receive the benefit of the extra four allocation points. The increase in transplantation of sensitized patients was observed despite a reduction in the number of offers proportional to their CPRA.

Interestingly, while there was an overall reduction in the rate of positive crossmatches among candidates with 0% PRA/CPRA, 1288 patients with 0% CPRA (Table 1) still declined kidney offers due to a positive crossmatch in the 6 months following CPRA implementation. This result is surprising because an unsensitized patient should not have a positive crossmatch. With sensitive solid-phase tests for HLA-specific antibody, the unsensitized patient can be very accurately identified and the virtual crossmatch for unsensitized patients should be more reliable than an actual crossmatch, which is subject to false positive reactions due to non-HLA-specific antibodies.

Some patients in the 0% CPRA group may have antibodies directed only against HLA-C, -DQ alpha chain or -DP locus antigens, which either do not result in a CPRA value >0% in the case of HLA-C or which cannot be represented as unacceptable antigens. Some patients may have antibodies that do not themselves reach the threshold of being unacceptable, but when two or more of the target HLA antigens are present in a donor, a positive crossmatch could result. It seems likely, however, that a substantial portion of patients in this group were not tested or did not have unacceptable antigens listed. Unfortunately these alternatives cannot be distinguished from available data. Clearly, the current results suggest that there is a benefit to entering unacceptable antigens for all sensitized patients.

With time, we can expect that the virtual positive crossmatch prediction will improve as programs and their laboratories examine unexpected positive crossmatches and adjust their thresholds. Including accurate HLA-C, -DQ alpha chain and -DP types for the donor should reduce predictably positive crossmatches among patients who have become sensitized to those antigens. Molecular HLA-typing methods are being more widely utilized and can be added to the donor testing procedures in most laboratories.

Figure 1 shows an increase in the number of very broadly sensitized (>95% PRA/CPRA) registrants on the waitlist during and after implementation of CPRA compared with the earlier time periods. This change may be due in part to the fact that CPRA reflects the actual distribution of both HLA class I and class II unacceptable HLA antigens more accurately than the panels used for measured PRA. PRA panels were designed to include a complete representation of either HLA class I or HLA class II antigens separately, which meant that the most common antigens were underrepresented and the rare antigens were overrepresented. It also meant that the class I and class II antigens were represented in different PRA scores. It is notable that the percentage of very broadly (>95%) sensitized patients was nearly the same during the 6-month periods before and after CPRA was implemented (Figure 1), but the rate of transplantation fell from 97 to 69 transplants per 1000 patient-years. The CPRA probably represents a truer estimate of transplantability for the very broadly sensitized patients than measured PRA.

We conclude that the introduction of CPRA has facilitated and expanded strategies that were already utilized at many centers in the United States. CPRA introduced accountability into the measure of sensitization on a national scale by preventing offers from deceased donors expressing unacceptable antigens. CPRA has provided consistency in the definition of sensitization because the values for all candidates are derived from OPTN donor frequencies in proportion to the national racial/ethnic donor distribution. However, it is unlikely that CPRA is applied uniformly, as the determination of unacceptable risk is left to the individual transplant programs and their affiliated laboratories. Greater uniformity may come as experience accrues and data are disseminated. The reduction in positive crossmatches nationwide and the increase in transplants to sensitized patients are very encouraging. We remain cautious that there may be some bolus effect in the observed increase in the transplant rate of broadly sensitized patients due to the accrual of substantial waiting time among this group of patients, such that when a compatible donor is available, the combination of the extra allocation points, waiting time points and a high probability of a negative crossmatch is facilitating their transplantation. Therefore, we might see a decline as the patients with very high CPRA values accumulate and do not receive any offers. Other factors, including the elimination of mandatory sharing for zero HLA mismatched kidneys except for sensitized patients, may also have affected patterns of transplantation among broadly sensitized patients.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Data and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure:
  8. References

These analyses represent a portion of the data gathering and analysis efforts of the OPTN/UNOS Histocompatibility Committee for the purpose of monitoring implementation of CPRA. J.M.C. is the past Committee Chair, A.Y.K. is the UNOS biostatistician, N.L.R. is the current Chair and M.S.L. is a former chair. We appreciate the efforts of the Histocompatibility Committee members during the past 6 years who have all worked hard on the development and implementation of CPRA.

Disclosure:

  1. Top of page
  2. Abstract
  3. Data and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure:
  8. References

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

  1. Top of page
  2. Abstract
  3. Data and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosure:
  8. References